Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000803734 | SCV000943619 | pathogenic | Charcot-Marie-Tooth Neuropathy X | 2021-04-29 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro70 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10873293, 21692908, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJB1 protein function. This variant has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 18636082, Invitae). ClinVar contains an entry for this variant (Variation ID: 637604). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with serine at codon 70 of the GJB1 protein (p.Pro70Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. |
| Ambry Genetics | RCV002422675 | SCV002730227 | uncertain significance | Inborn genetic diseases | 2020-03-03 | criteria provided, single submitter | clinical testing | The p.P70S variant (also known as c.208C>T), located in coding exon 1 of the GJB1 gene, results from a C to T substitution at nucleotide position 208. The proline at codon 70 is replaced by serine, an amino acid with similar properties. This variant has been detected in a female individual with a diagnosis of Charcot-Marie-Tooth neuropathy (Houlden H et al. Eye (Lond), 2009 Apr;23:966-74). Additionally, this variant was noted in a male individual initially presenting with features of an inflammatory neuropathy who was later noted to also have features of Charcot-Marie-Tooth neuropathy, as well as his mother who presented with diminished Achilles tendon reflexes and mild bilateral peroneal weakness (Kokubun N et al. Clin Exp Neuroimmunol, 2020 Jan; DOI: 10.1111/cen3.12566). Additional alterations have also been reported at this amino acid position in patients with Charcot-Marie-Tooth neuropathy (Ionasescu VV. Cell Biol. Int., 1998 Nov;22:807-13; Karadima G et al. J. Neurol., 2006 Feb;253:263-4; Siskind CE et al. J. Peripher. Nerv. Syst., 2011 Jun;16:102-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Inherited Neuropathy Consortium | RCV000789863 | SCV000929248 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |